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Pre-conference Workshop Cyclodextrins and Cyclodextrin Derivatives as Pharmaceutical Excipients: Toxicological and Regulatory Issues Saturday, June 2nd 2012 Location: Icelandair Hotel Reykjavik Natura (formerly Hotel Loftleidir) Program: 9:00 -10:00 Thorsteinn Loftsson University of Iceland Cyclodextrin metabolism and pharmacokinetics 10:00 – 11:00 Eva Fenyvesi CycloLab Ltd. Cyclodextrin derivatives: substitution degree and pattern 11:00 – 12:00 Jyrki Heinämäki University of Tartu New pharmaceutical excipients: Development and regulatory perspectives 12:00 – 13:30 Brunch 13:30 – 14:30 Piotr Kozarewicz European Medicines Agency New excipients - regulatory aspects and EMA experience 14:30 – 15:30 Marcus E. Brewster Johnson & Johnson Registration Experiences with Hydroxypropyl-βcyclodextrin 15:30 – 17:00 All Discussions Sponsored by Cyclodextrin metabolism and pharmacokinetics Thorsteinn Loftsson Faculty of Pharmaceutical Sciences, University of Iceland, Hofsvallagata 53, IS-107 Reykjavik, Iceland Cyclodextrins (CDs) possess many of the same physicochemical and biological characteristics as water-soluble linear dextrins. However, due to their cyclic structure, they are more resistant towards both enzymatic as well as non-enzymatic hydrolysis than linear dextrins such as dextran. CDs are resistant to β-amylases that hydrolyze starch from the non-reducing end, but are slowly hydrolyzed by α-amylases that hydrolyze starch from within the carbohydrate chain. The hydrolytic rate depends on the ring size and fraction of free CD. All the natural CDs and their derivatives are susceptible to bacterial digestion in the gastrointestinal tract. CDs are mainly (more than about 90%) excreted unchanged with urine via glomerular filtration after parenteral administration. Most likely any remaining CD is eliminated by other pathways such as by liver metabolism and biliary excretion via the gastrointestinal tract, analogous to excretion of the low molecular weight dextrans. The pharmacokinetics of CDs is very similar to that of linear dextrins of comparable molecular weight. In humans the half-life (t½) of the elimination phase ranges from about 1.4 to 2 hours and the volume of distribution (VD) is about 0.2 L/kg for all CDs tested. The pharmacokinetic studies show that over 90% of parenterally administered CD will be eliminated from the body within about 6 hours and over 99.9% within 24 hours. Thus, no accumulation of CD will be observed in individuals with normal kidney function, even at high doses. However, CD accumulation will be observed in severely renally impaired patients, i.e. individuals with renal clearance below about 10 ml/min. References 1. Frömming, K. H., Szejtli, J., 1994. Cyclodextrins in pharmacy, Kluwer Academic Publishers, Dordrecht. 2. Irie, T., Uekama, K., 1997. Pharmaceutical applications of cyclodextrins. III. Toxicological issues and safety evaluation. J. Pharm. Sci., 86, 147-162. 3. Stella, V. J., He, Q., 2008. Cyclodextrins. Tox. Pathol., 36, 30-42. 4. Loftsson, T., Brewster, M. E., 2010. Pharmaceutical applications of cyclodextrins: basic science and product development. J. Pharm. Pharmacol., 62, 1607-1621. Cyclodextrin derivatives: substitution degree and pattern Eva Fenyvesi CycloLab Ltd., H-1097 Budapest, Illatos út 7, Hungary Cyclodextrin derivatives are usually mixtures of hundreds of isomers. They can be characterized by the average degree of substitution and a fingerprint of the distribution of the various isomers. The lecture will cover both the methods for characterization of these properties in the case of hydroxypropyl and methylated cyclodextrins and the effect of the degree and pattern of substitution on the pharmaceutically relevant properties (solubilizing effect on drugs and cell membrane constituents such as cholesterol and phospholipids). An overview on the regulatory requirements concerning the degree and pattern of substitution will be given. The mixed derivatives having both ionic and anionic substituents as a strategy to reduce toxicity will be discussed. The selfaggregation behavior will be also compared. New pharmaceutical excipients: Development and regulatory perspectives Jyrki Heinämäki Department of Pharmacy, Faculty of Medicine, University of Tartu, Nooruse 1, 50411 Tartu, Estonia Pharmaceutical excipients are chemical substances apart from the active substance and they are designed to be therapeutically inert. Excipients are “pharmaceutical necessities” that have various important functions in a medicine. Today, new and specialized areas of drug delivery (nanoparticles, dendrimers, drug impregnated adhesives and coatings, tissue repair products, etc.), provide opportunity and necessitate the novel use of excipients and/or the development of new excipients. New excipients, however, require a thorough characterisation and documentation with regard to their functionality, physicochemistry and safety like a new active substance. This lecture will review development of new pharmaceutical excipients and regulatory actions to approve these excipients. The differences of European Medicines Agency (EMA) and US Food and Drug Administration (FDA) guidances on quality and safety testing of new excipients will be compared and discussed. Four case studies will be presented as examples of implementation of novel excipients including two new chemical excipients (polyoxyl 15 hydroxystearate and sulfobutyl ether cyclodextrin), a new graft co-polymer (polyvinyl caprolactam-polyvinyl acetate-PEG), and a new co-processed excipient (silicified microcrystalline cellulose). Potential toxicological concerns for impurity safety of new excipients will be also discussed with a special reference set impurity safe limits. References 1. European Medicines Agency (EMA). Committee for Medicinal Products for Human Use (CMPH). Guideline on excipients in the dossier for application for marketing authorisation 2008: 1-12 2. Osterberg RE, DeMerlis CC, Hobson DW et al. Trends in excipient safety evaluation. Int J Toxicol 2011;30:600-10 3. Koo MY, Varia SA. Case studies with new excipients: development, implementation and regulatory approval. Therapeutic Delivery 2011;2(7):949-56. New excipients – regulatory aspects and EMA experience Piotr Kozarewicz European Medicines Agency, 7 Westferry Circus, Canary Wharf, London E14 4HB, United Kingdom Excipients constitute necessary and important components of medicinal products. Although not pharmacologically active, they can enhance product performance by assuring the stability of the active substance, or to protect against microbial contamination during use, or to optimise the delivery or the kinetics of the active substance and therefore can influence the bioavailability. It is not a homogenous group of substances, and various subgroups can be distinguished based on their function in medicinal products or by the length of their use, e.g. well established excipients vs novel (or new) ones. The nature of excipients used in pharmaceutical formulations is changing from traditional, compendial substances to more complex or sophisticated compounds designed to perform specific functions within the medicinal product. These substances, classified as novel excipients, are increasingly being developed purely for pharmaceutical use. In accordance with the current guidelines, a novel excipient is an excipient which is used for the first time in a drug product, or by a new route of administration (ICH). It may be a new chemical entity or a well established one which has not yet been used for human administration and/or for a particular human administration pathway in the EU and/or outside the EU. Why the novel excipients are being developed? The need for more focused or targeted drug delivery and use of new technology to meet these needs, new lipophilic and high molecular weight compounds, compounds with low permeability, innovative proteins or micro-/nano-sized carrier systems trigger development of more sophisticated delivery systems and/or use of novel excipients. The use of novel excipients can be seen as a challenge, as the amount of information required in support of a marketing authorization is much more comprehensive than for an established excipient. According to the EU legislation, novel excipient is regarded as a new substance which must be subjected to the full evaluation, similar to new active substances. Full details of manufacture, characterisation, and controls, with cross references to supporting safety data, both non-clinical and clinical, are expected to be provided according to the active substance format and to be presented as a stand-alone document. Additional information on toxicity studies with the novel excipient is expected to be provided in non-clinical part of the dossier. This requires acute toxicity studies, subchronical and chronical studies, genotoxicity studies, reproductive toxicity studies and ADME. As for any active substance, the principles of risk-benefit assessment apply to excipients included in medicinal products. Although novel excipients are developed for pharmaceutical use, they are not frequently seen in medicinal products. Stricter requirements lead to perception that the use of novel excipients makes evaluation more complex and may cause delays in the approval process. However if everything is done properly, using a novel excipient is no more risky than an established one. This presentation aims to provide guidance on regulatory requirements for novel excipients in the EU (what needs to be provided) and characterise the impact on the approval process caused by inclusion of novel excipients in medicinal products (what the process will look like). References: 1. Annex 1 of the Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use. 2. Guideline on excipients in the dossier for application for marketing authorisation of a medicinal product (EMEA/CHMP/QWP/396951/2006). 3. CHMP Scientific Article 5(3) opinion on the potential risks of carcinogens, mutagens and substances toxic to reproduction when these substances are used as excipients of medicinal products for human use (EMEA/CHMP/SWP/146166/2007). Registration Experiences with Hydroxypropyl-β-cyclodextrin Marcus E. Brewster Pharmaceutical Development and Manufacturing Sciences, Janssen Research and Development, Johnson & Johnson, Turnhoutseweg 30, Beerse 2340 Belgium In order to achieve appropriate levels of solubilization, dissolution rate and potential supersaturation, excipients are often required. Excipients are components of a dosage form which are included for a variety of reasons and are usually not directly associated with the activity of the selected drug substance. These materials, unlike the active pharmaceutical ingredient (API), have no regulatory status in and of themselves. In the US, their use is generally supported by widespread experience with these materials based on: (1) being recognized as “generally regarded as safe (GRAS)” by the FDA and other agencies (USA 21CFR182, 184 and 186), (2) being approved as a food additive by the FDA or other agencies (21CFR171), (3) being present in an approved drug product. In this instance, the use of the excipient, without additional data, is limited to circumstances where the same material is used in the same administration route, at the same level of exposure, for the same duration and in the same patient population. The nature and extent of toxicology needed to use an excipient is included in “Guidance for Industry – Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients” (FDA 2005). Hydroxypropyl-β-cyclodextrin is compendial in the European Pharmacopeia (EP) as well as the United States Pharmacopeia (USP/NF) where its official designation is hydroxypropylbetadex. The compound is also available in the FDA List of Inactive Ingredients. Janssen Pharmaceutical maintains a drug master file (DMF) containing information on this material which has allowed its successful use as an excipients in multiple products. Information that was considered important in this regard include analytical data as well as toxicology evaluation - mutagenicity, single and multiple doses to various animal species, reproductive and embryotoxicology, carcinogenicity assessments, pharmacodynamics, pharmacokinetics and toxicokinetics, local irritation and tolerance as well as a number of specialty studies. A brief description and history of the regulatory submission of the data package will be provided. References 1. M. Brewster, T. Loftsson. Cyclodextrins as pharmaceutical solubilizers. Drug Deliv Rev 2007;59:645-666. Adv